17β-estradiol, which is naturally formed in the ovaries [also referred to as E2], has a general proliferation-enhancing action in humans and animals. In addition to controlling the female cycle, it has, i.a., a homeostatic effect on the metabolism of the bone, while also preventing the formation of atherotic plaques on vessel endothelia.
During menopause, estradiol levels decrease due to cessation of ovarial function. In the absence of sufficiently high estradiol levels in the blood, the activity of the osteoclasts, and thus breakdown of the bone mass—so-called “osteoporosis”—predominates in the bone tissue, which is accompanied by an increased risk of skeletal breakage.
In recent times it was found that this syndrome of osteoporosis brought about by lack of sexual hormone is not restricted to women, but that from a certain advanced age, osteoporosis brought about by lack of sexual hormone also occurs in men, in particular in connection with ailments of the prostate.
The classical prophylaxis and therapy in woman consists in supplementing natural estrogen by administration of natural and synthetic estrogens. In particular, for prophylactic purposes, calcium doses of approx. 1 gram of calcium per day are applied in man and woman.
Administration of estrogens such as, e.g., 17β-estradiol or the chemical derivatives thereof is, however, accompanied by the known grave side effects of uterotrophic effect, increased risk of thrombo-embolism, weight gain, and the like.
There have been many attempts reported in the prior art to find medicaments capable of producing an estrogen-type effect either without undesireable side effects, or with strongly diminished undesirable side effects. Plant extracts have been frequently used that exhibit the desired action of osteoporosis prophylaxis, but not, however, the undesirable uterotrophic effects.
Thus, for example, WO 99/47149 (=EP 1064009A1) to the present applicant discloses that extracts from iridaceae, in particular from Cimicifuga racemosa and Belamcanda chinensis and of the isoflavonoid tectorigenin contained therein, do not have an estrogen-type effect on the uterus, yet do so in the hypothalamo-hypophysary axis, in the cardiovascular system, and in the bone, so that these plant extracts may be employed for the prophylaxis and therapy of osteoporosis.
Moreover, calcium preparations for the prophylaxis of osteoporosis are known in the prior art. A pharmaceutical formulation to this end, besides an injection solution, is preferably an effervescent tablet for oral application. Such effervescent tablets may, e.g., have the following composition:
Tablets with 500 mg of Ca2+: 1250 mg of calcium carbonate, 2050 mg of citric acid, further constituents: lactose 1H2O, macrogol 6000, Povidon, sodium cyclamate, saccharine sodium 2H2O, Dimeticon 350, highly dispersed silica, macrogol stearate 400, sorbic acid, flavoring agents.
Tablets with 1000 mg of Ca2+: 4954 mg of calcium lactogluconate, 900 mg of calcium carbonate, and further constituents: citric acid, sodium cyclamate, saccharine sodium, mannitol, macrogol 4000, sodium hydrogencarbonate, flavoring agents.
In order to spare patients multiple applications, and also for cost reasons, a combination of calcium preparations having a high Ca2+ content with dry plant extract having an anti-osteoporosis effect would be desirable.
Simple admixture to a calcium effervescent tablet mass, however, is foiled by the high sensitivity of the dry extracts to acids in an aqueous medium on the one hand, and by the poor water solubility of many dry extracts in an acidic medium on the other hand. Moreover the humidity-sensitive effervescent masses are imperiled by the highly hygroscopic dry extracts.
Encapsulation in customary gelatin capsules must equally be ruled out as the capsules are generally not water vapor tight and thus would decompose and/or agglomerate the dry plant extract, so that the pharmaceutical quality would cease to be ensured due to undefined bioavailability, release, and/or effectivity. Moreover the stability of such gelatin capsules is not warranted, for it is reported in literature, e.g., that instances of crosslinking with the gelatin occur when plant extracts are encapsulated in gelatin, and significant changes of the ingredients result from water absorption by the dry extract.
Thus, for example, a sugar-coated tablet, or dragée, formulation consisting of a mixture of calcium and dry plant extract would be optimal. As was mentioned above, significant calcium contents of 500 mg Ca2+ and more, together with the relatively large amounts of auxiliaries for dragée manufacture, would result in large dragée sizes and weights which would not be acceptable to patients.
Known solid formulations are combination preparations of calcium with vitamin D3 in the form of chewing tablets, e.g. as Ossofortin® forte chewing tablets by the company Strathmann AG+Co., Sellhopsweg 1, D-22459 Hamburg.
Such chewing tablets for supportive treatment of osteoporosis have the following composition:
1500.3 mg of calcium carbonate (corresponding to 600 mg of Ca++), Colecalciferol dry concentrate (100 000 I.U./g) 400 I.U., further constituents: xylitol, corn starch, saccharine sodium, flavoring agent, magnesium stearate.
Up to the present, no prior art has taught the combination of calcium preparations with plant extracts suited for the above described prophylaxis and/or therapy of osteoporosis, for the above named reasons.